Growth hormone secretagogues

ABSTRACT

The invention relates to compounds of formula I 
                         
which are useful for elevating the plasma level of growth hormone in a mammal as well as for the treatment of growth hormone secretion deficiency, growth retardation in child and metabolic disorders associated with growth hormone secretion deficiency.

This application is a continuation of U.S. application Ser. No.09/880,498, filed Jun. 13, 2001, now U.S. Pat. No. 6,861,409 whichclaims priority to U.S. provisional application Nos. 60/234,928 filed onSep. 26, 2000, and 60/211,326 filed on Jun. 13, 2000.

FIELD OF THE INVENTION

The invention relates to compounds, which are useful for administrationto a mammal thereby elevating the plasma level of growth hormone.

BACKGROUND OF THE INVENTION

(a) Description of Prior Art

Growth hormone (GH) or somatotropin, secreted by the pituitary glandconstitute a family of hormones which biological activity is fundamentalfor the linear growth of a young organism but also for the maintenanceof the integrity at its adult state. GH acts directly or indirectly onthe peripheral organs by stimulating the synthesis of growth factors(insulin-like growth factor-I or IGF-I) or of their receptors (epidermalgrowth factor or EGF). The direct action of GH is of the type referredto as anti-insulinic, which favors the lipolysis at the level of adiposetissues. Through its action on IGF-I (somatomedin C) synthesis andsecretion, GH stimulates the growth of the cartilage and the bones(structural growth), the protein synthesis and the cellularproliferation in multiple peripheral organs, including muscles and theskin. Through its biological activity, GH participates within adults atthe maintenance of a protein anabolism state, and plays a primary rolein the tissue regeneration phenomenon after a trauma.

The decrease of GH secretion with the age, demonstrated in humans andanimals, favors a metabolic shift towards catabolism which initiates orparticipates to the ageing of an organism. The loss in muscle mass, theaccumulation of adipose tissues, the bone demineralization, the loss oftissue regeneration capacity after an injury, which are observed inelderly, correlate with the decrease in the secretion of GH.

GH is thus a physiological anabolic agent absolutely necessary for thelinear growth of children and which controls the protein metabolism inadults.

Growth hormone (GH) secretion is regulated by two hypothalamic peptides:GH-releasing hormone (GHRH), which exerts stimulatory effect on GHrelease and somatostatin which exhibits an inhibitory influence. In thelast few years, several investigators have demonstrated that GHsecretion can also be stimulated by synthetic oligopeptides termedGH-releasing peptides (GHRP) such as hexarelin and various hexarelinanalogs (Ghigo et al., European Journal of Endocrinology, 136, 445-460,1997). These compounds act through a mechanism which is distinct fromthat of GHRH (C. Y. Bowers, in “Xenobiotic Growth HormoneSecretagogues”, Eds. B. Bercu and R. F. Walker, Pg. 9-28,Springer-Verlag, New York 1996) and by interaction with specificreceptors localized in the hypothalamus and pituitary gland ((a) G.Muccioli et al., Journal of Endocrinology, 157, 99-106, 1998; (b) G.Muccioli, “Tissue Distribution of GHRP Receptors in Humans”, AbstractsIV European Congress of Endocrinology, Sevilla, Spain, 1998). Recentlyit was demonstrated that GHRP receptors are present not only in thehypothalamo-pituitary system but even in various human tissues notgenerally associated with GH release (G. Muccioli et al., see above(a)).

GHRPs and their antagonists are described, for example, in the followingpublications: C. Y. Bowers, supra, R. Deghenghi, “Growth HormoneReleasing Peptides”, ibidem, 1996, pg. 85-102; R. Deghenghi et al.,“Small Peptides as Potent Releasers of Growth Hormone”, J. Ped. End.Metab., 8, pg. 311-313, 1996; R. Deghenghi, “The Development ofImpervious Peptides as Growth Hormone Secretagogues”, Acta Paediatr.Suppl., 423, pg. 85-87, 1997; K. Veeraraganavan et al., “Growth HormoneReleasing Peptides (GHRP) Binding to Porcine Anterior Pituitary andHypothalamic Membranes”, Life Sci., 50, Pg. 1149-1155, 1992; and T. C.Somers et al., “Low Molecular Weight Peptidomimetic Growth HormoneSecretagogues, WO 96/15148 (May 23, 1996).

The human GH has been produced by genetic engineering for about tenyears. Until recently most of the uses of GH were concerned with growthdelay in children and now the uses of GH in adults are studied. Thepharmacological uses of GH, GHRPs and growth hormone secretagogues andmay be classified in the following three major categories.

(b) Children Growth

Treatments with recombinant human growth hormone have been shown tostimulate growth in children with pituitary dwarfism, renalinsufficiencies, Tumer's syndrome and short stature. Recombinant humanGH is presently commercialized in Europe and in the United States forchildren's growth retardation caused by a GH deficiency and forchildren's renal insufficiencies. The other uses are under clinicaltrial investigation.

(c) Long Term Treatment for Adults and Elderly Patients

A decrease in GH secretion causes changes in body composition duringaging. Preliminary studies of one-year treatment with recombinant humanGH reported an increase in the muscle mass and in the thickness of skin,a decrease in fat mass with a slight increase in bone density in apopulation of aged patients. With respect to osteoporosis, recentstudies suggest that recombinant human GH does not increase bonemineralization but it is suggested that it may prevent bonedemineralization in post-menopausal women. Further studies are currentlyunderway to demonstrate this theory.

(d) Short Term Treatment in Adults and Elderly Patients

In preclinical and clinical studies, growth hormone has been shown tostimulate protein anabolism and healing in cases of burn, AIDS andcancer, in wound and bone healing.

GH, GHRPs and growth hormone secretagogues are also intended forveterinary pharmacological uses. GH, GHRPs and growth hormonesecretagogues stimulate growth in pigs during its fattening period byfavoring the deposition of muscle tissues instead of adipose tissues andincrease milk production in cows, and this without any undesired sideeffects which would endanger the health of the animals and without anyresidue in the meat or milk being produced. The bovine somatotropin(BST) is presently commercialized in the United States.

Most of the clinical studies presently undertaken were conducted withrecombinant GH. The GHRPs and growth hormone secretagogues areconsidered as a second generation product destined to replace in thenear future the uses of GH in most instances. Accordingly, the use ofGHRPs and growth hormone secretagogues present a number of advantagesover the use of GH per se.

Therefore, there is a need for compounds which, when administered to amammal, act as growth hormone secretagogues.

SUMMARY OF THE INVENTION

The present invention relates to new compounds which act as growthhormone secretagogues and, in general, to a method for elevating theplasma level of growth hormone in a mammal by administering thereto oneor more of the compounds according to the invention. The invention alsorelates to methods for the treatment of growth hormone secretiondeficiency, for promoting wound healing, recovery from surgery orrecovery from debilitating illnesses, by administering to a mammal oneof these compounds in a therapeutically effective amount.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In this description, the following abbreviations are used: D is thedextro enantiomer, GH is growth hormone, Boc is tert-butyloxycarbonyl, Zis benzyloxycarbonyl, N-Me is N-methyl, Pip is4-amino-piperidine-4-carboxylate, Inip is isonipecotyl, i.e.piperidine-4-carboxylate, Aib is α-amino isobutyryl, Nal isβ-naphthylalanine, Mrp is 2-Methyl-Trp, and Ala, Lys, Phe, Trp, His,Thr, Cys, Tyr, Leu, Gly, Ser, Pro, Glu, Arg, Val and Gln are the aminoacids alanine, lysine, phenylalanine, tryptophan, histidine, threonine,cysteine, tyrosine, leucine, glycine, serine, proline, glutamic acid,arginine, valine and glutamine, respectively. Furthermore gTrp is agroup of the formula

and gMrp a group of the formula

wherein * means a carbon atom which, when a chiral carbon atom, has a Ror S configuration. The compounds of the invention are of the generalformula I:

wherein * means a carbon atom which, when a chiral carbon atom, has a Ror S configuration, one of R¹ and R³ is an hydrogen atom and the otheris a group of formula II

R² is a hydrogen atom, a linear or branched C₁-C₆ alkyl group, an arylgroup, a heterocyclic group, a cycloalkyl group, a (CH₂)_(n)-aryl group,a (CH₂)_(n)-heterocyclic group, a (CH₂)_(n)-cycloalkyl group, amethylsulfonyl group, a phenylsulfonyl group, a C(O)R⁸ group or a groupaccording to one or formulas III to VIII below:

R⁴ is a hydrogen atom or a linear or branched C₁-C₄-alkyl group, R⁵ is ahydrogen atom, a linear or branched C₁-C₄ alkyl group, a (CH₂)_(n)-arylgroup, a (CH₂)_(n)-heterocycle group, a (CH₂)_(n)-cycloalkyl group or anamino group, R⁶ and R⁷ are independently from each other a hydrogen atomor a linear or branched C₁-C₄-alkyl group, R⁸ is a linear or branchedC₁-C₆-alkyl group, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ areindependently from each other a hydrogen atom or a linear or branchedC₁-C₄-alkyl group, m is 0, 1 or 2 and n is 1 or 2.

A preferred embodiment of the invention are compounds wherein R² ishydrogen, R³ is a group of formula II and m is 0. Particularly preferredare compounds, wherein linear or branched C₁-C₄ alkyl is methyl, linearor branched C₁-C₆ alkyl is methyl, ethyl or i-butyl, aryl is phenyl ornaphthyl, cycloalkyl is cyclohexyl and the heterocyclic group is a4-piperidinyl or 3-pyrrolyl group.

Specifically preferred compounds of the invention include the following:

-   H-Aib-D-Trp-D-gTrp-CHO:

-   N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃:

-   N-Me-Aib-D-Trp-N-Me-D-gTrp-C(O)CH₃:

In accordance with the present invention, it has been found that thecompounds of the invention are useful for elevating the plasma level ofgrowth hormone in a mammal. Furthermore the compounds of the presentinvention are useful for the treatment of growth hormone secretiondeficiency, growth retardation in child and metabolic disordersassociated with growth hormone secretion deficiency, in particular inaged subjects.

Pharmaceutically acceptable salts of these compounds can be also used,if desired. Such salts include organic or inorganic addition salts, suchas hydrochloride, hydrobromide, phosphate, sulfate, acetate, succinate,ascorbate, tartrate, gluconate, benzoate, malate, fumarate, stearate orpamoate salts.

Pharmaceutical compositions of the invention are useful for elevatingthe plasma level of growth hormone in a mammal, including a human, aswell for the treatment of growth hormone secretion deficiency, growthretardation in child and metabolic disorders associated with growthhormone secretion deficiency, in particular in aged subjects. Suchpharmaceutical compositions can comprise a compound according to thepresent invention or a pharmaceutically acceptable salt thereof, orcombinations of compounds according to the present invention orpharmaceutically acceptable salts thereof, optionally in admixture witha carrier, excipient, vehicle, diluent, matrix, or delayed releasecoating. Examples of such carriers, excipients, vehicles, and diluents,can be found in Remington's Pharmaceutical Sciences, 18th Edition, A. R.Gennaro, Ed., Mack Publishing Company, Easton, Pa., 1990.

The pharmaceutical compositions of the invention can comprise anadditional growth hormone secretagogue. Examples for suitable additionalgrowth hormone secretagogues are Ghrelin (cf. M. Kojima et al., Nature,402 (1999), 656-660), GHRP-1, GHRP-2 and GHRP-6.

Ghrelin:Gly-Ser-Ser(O-n-octanoyl)-Phe-Leu-Ser-Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu-Ser-Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg

GHRP-1: Ala-His-D-β-Nal-Ala-Trp-D-Phe-Lys-NH₂

GHRP-2: D-Ala-D-β-Nal-Ala-Trp-D-Phe-Lys-NH₂

GHRP-6: His-D-Trp-Ala-Trp-D-Phe-Lys-NH₂

Any of the compounds according to the present invention can beformulated by the skilled in the art to provide medicaments which aresuitable for parenteral, buccal, rectal, vaginal, transdermal, pulmonaryor oral routes of administration.

The type of formulation of the medicament containing the compound can beselected according to the desired rate of delivery. For example, if thecompounds are to be rapidly delivered, the nasal or intravenous route ispreferred.

The medicaments can be administered to mammals, including humans, at atherapeutically effective dose which can be easily determined by one ofskill in the art and which can vary according to the species, age, sexand weight of the treated patient or subject as well the route ofadministration. The exact level can be easily determined empirically.

EXAMPLES

The following examples illustrate the efficacy of the most preferredcompounds used in the treatment of this invention.

Example 1 H-Aib-D-Trp-D-gTrp-CHO

Total synthesis (percentages represent yields obtained in the synthesisas described below):

Z-D-Trp-NH₂

Z-D-Trp-OH (8.9 g; 26 mmol; 1 eq.) was dissolved in DME (25 ml) andplaced in an ice water bath to 0° C. NMM (3.5 ml; 1.2 eq.), IBCF (4.1ml; 1.2 eq.) and ammonia solution 28% (8.9 ml; 5 eq.) were addedsuccessively. The mixture was diluted with water (100 ml), and theproduct Z-D-Trp-NH₂ precipitated. It was filtered and dried in vacuo toafford 8.58 g of a white solid.

Yield=98%. C₁₉H₁₉N₃O₃, 337 g·mol⁻¹. Rf=0.46 {Chloroform/Methanol/AceticAcid (180/10/5)}. ¹H NMR (250 MHZ, DMSO-d⁶): δ 2.9 (dd, 1H, H_(β),J_(ββ′)=14.5 Hz; J_(βα)=9.8 Hz); 3.1 (dd, 1H, H_(β′), J_(β′β)=14.5 Hz;Jβ′α=4.3 Hz); 4.2 (sextuplet, 1H, H_(α)); 4.95 (s, 2H, CH₂ (Z)); 6.9-7.4(m, 11H); 7.5 (s, 1H, H²); 7.65 (d, 1H, J=7.7 Hz); 10.8 (s, 1H, N¹H).Mass Spectrometry (Electrospray), m/z 338 [M+H]⁺, 360 [M+Na]⁺, 675[2M+H]⁺, 697 [2M+Na]⁺.

Boc-D-Trp-D-Trp-NH₂

Z-D-Trp-NH₂ (3 g; 8.9 mmol; 1 eq.) was dissolved in DMF (100 ml). HCl36% (845 μl; 1.1 eq.), water (2 ml) and palladium on activated charcoal(95 mg, 0.1 eq.) were added to the stirred mixture. The solution wasbubbled under hydrogen for 24 hr. When the reaction went to completion,the palladium was filtered on celite. The solvent was removed in vacuoto afford HCl, H-D-Trp-NH₂ as a colorless oil.

In 10 ml of DMF, HCl, H-D-Trp-NH₂ (8.9 mmol; 1 eq.), Boc-D-Trp-OH (2.98g; 9.8 mmol; 1.1 eq.), NMM (2.26 ml; 2.1 eq.) and BOP (4.33 g; 1.1 eq.)were added successively. After 1 hr, the mixture was diluted with ethylacetate (100 ml) and washed with saturated aqueous sodium hydrogencarbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), andsaturated aqueous sodium chloride (100 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo to afford4.35 g of Boc-D-Trp-D-Trp-NH₂ as a white solid.

Yield=85%. C₂₇H₃₁N₅O₄, 489 g·mol⁻¹. Rf=0.48 {Chloroform/Methanol/AceticAcid (85/10/5)}. ¹H NMR (200 MHZ, DMSO-d⁶): δ 1.28 (s, 9H, Boc);2.75-3.36 (m, 4H, 2 (CH₂)_(β); 4.14 (m, 1H, CH_(α)); 4.52 (m, 1H,CH_(α′)); 6.83-7.84 (m, 14H, 2 indoles (11H), NH₂, NH (urethane) and NH(amide)); 10.82 (d, 1H, J=2 Hz, N¹H); 10.85 (d, 1H, J=2 Hz, N¹H). MassSpectrometry (Electrospray), m/z 490 [M+H]⁺, 512 [M+Na]⁺, 979 [2M+H]⁺.

Boc-D-(NiBoc)Trp-D-(NiBoc)Tr -NH₂

Boc-D-Trp-D-Trp-NH₂ (3 g; 6.13 mmol; 1 eq.) was dissolved inacetonitrile (25 ml). To this solution, di-tert-butyl-dicarbonate (3.4g; 2.5 eq.) and 4-dimethylaminopyridine (150 mg; 0.2 eq.) weresuccessively added. After 1 hr, the mixture was diluted with ethylacetate (100 ml) and washed with saturated aqueous sodium hydrogencarbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), andsaturated aqueous sodium chloride (200 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/hexane {5/5} to afford 2.53 g ofBoc-D-(N^(i)Boc)Trp-D-(N^(i)Boc)Trp-NH₂ as a white solid.

Yield=60%. C₃₇H₄₇N₅O₈, 689 g·mol⁻¹. Rf=0.23 {ethyl acetate/hexane(5/5)}. ¹H NMR (200 MHZ, DMSO-d⁶): δ 1.25 (s, 9H, Boc); 1.58 (s, 9H,Boc); 1.61 (s, 9H, Boc); 2.75-3.4 (m, 4H, 2 (CH₂)_(β)); 4.2 (m, 1H,CH_(α′)); 4.6 (m, 1H, CH_(α)); 7.06-8 (m, 14H, 2 indoles (10H), NH(urethane), NH and NH₂ (amides)). Mass Spectrometry (Electrospray), m/z690 [M+H]⁺, 712 [M+Na]⁺, 1379 [2M+H]⁺, 1401 [2M+Na]⁺.

Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-H

Boc-D-(N^(i)Boc)Trp-D-(N^(i)Boc)Trp-NH2 (3 g; 4.3 mmol; 1 eq.) wasdissolved in the mixture DMF/water (18 ml/7 ml). Then, pyridine (772 μl;2.2 eq.) and Bis(Trifluoroacetoxy)IodoBenzene (2.1 g; 1.1 eq.) wereadded. After 1 hr, the mixture was diluted with ethyl acetate (100 ml)and washed with saturated aqueous sodium hydrogen carbonate (200 ml),aqueous potassium hydrogen sulfate (200 ml, 1M), and aqueous saturatedsodium chloride (200 ml). The organic layer was dried over sodiumsulfate, filtered and the solvent removed in vacuo.Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-H was used immediately for the nextreaction of formylation.

Rf=0.14 {ethyl acetate/hexane (7/3)}. C₃₆H₄₇N₅O₇, 661 g·mol⁻¹. ¹H NMR(200 MHZ, DMSO-d⁶): δ 1.29 (s, 9H, Boc); 1.61 (s, 18H, 2 Boc); 2.13 (s,2H, NH₂ (amine)); 3.1-2.8 (m, 4H, 2 (CH₂)_(β)); 4.2 (m, 1H, CH_(α′));4.85 (m, 1H, CH_(α)); 6.9-8 (m, 12H, 2 indoles (10H), NH (urethane), NH(amide)). Mass Spectrometry (Electrospray), m/z 662 [M+H]⁺, 684 [M+Na]⁺.

Boc-D-(N^(i)Boc)Trp-D-G(N^(i)Boc)Trp-CHO

Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-H (4.3 mmol; 1 eq.) was dissolvedin DMF (20 ml). Then, N,N-diisopropylethylamine (815 μl; 1.1 eq.) and2,4,5-trichlorophenylformate (1.08 g; 1.1 eq.) were added. After 30minutes, the mixture was diluted with ethyl acetate (100 ml) and washedwith saturated aqueous sodium hydrogen carbonate (200 ml), aqueouspotassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodiumchloride (200 ml). The organic layer was dried over sodium sulfate,filtered and the solvent removed in vacuo. The residue was purified byflash chromatography on silica gel eluting with ethyl acetate/hexane{5/5} to afford 2.07 g of Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-CHO as awhite solid.

Yield=70%. C₃₇H₄₇N₅O₈, 689 g·mol⁻¹. Rf=0.27{ ethyl acetate/hexane(5/5)}. ¹H NMR (200 MHZ, DMSO-d⁶): δ 1.28 (s, 9H, Boc); 1.6 (s, 9H,Boc); 1.61 (s, 9H, Boc); 2.75-3.1 (m, 4H, 2 (CH₂)_(β)); 4.25 (m, 1H,(CH)α_(A&B)); 5.39 (m, 0.4H, (CH)α′_(B)); 5.72 (m, 0.6H, (CH)α′_(A));6.95-8.55 (m, 14H, 2 indoles (10H), NH (urethane), 2 NH (amides), CHO(formyl)). Mass Spectrometry (Electrospray), m/z 690 [M+H]⁺, 712[M+Na]⁺, 1379 [2M+H]⁺.

Boc-Aib-D-Trp-D-gTrp-CHO

Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-CHO (1.98 g; 2.9 mmol; 1 eq.) wasdissolved in a mixture of trifluoroacetic acid (16 ml), anisole (2 ml)and thioanisole (2 ml) for 30 minutes at 0° C. The solvents were removedin vacuo, the residue was stirred with ether and the precipitated TFA,H-D-Trp-D-gTrp-CHO was filtered.

TFA, H-D-Trp-D-gTrp-CHO (2.9 mmol; 1 eq.), Boc-Aib-OH (700 mg; 1 eq.),NMM (2.4 ml; 4.2 eq.) and BOP (1.53 g; 1.2 eq.) were successively addedin 10 ml of DMF. After 1 hr, the mixture was diluted with ethyl acetate(100 ml) and washed with saturated aqueous sodium hydrogen carbonate(200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturatedaqueous sodium chloride (200 ml). The organic layer was dried oversodium sulfate, filtered and the solvent removed in vacuo. The residuewas purified by flash chromatography on silica gel eluting with ethylacetate to afford 1.16 g of Boc-Aib-D-Trp-D-gTrp-CHO as a white solid.

Yield=70%. C₃₁H₃₈N₆O₅, 574 g·mol⁻¹. Rf=0.26 {Chloroform/Methanol/AceticAcid (180/10/5)}. ¹H NMR (200 MHZ, DMSO-d⁶): δ 1.21 (s, 6H, 2 CH₃(Aib)); 1.31 (s, 9H, Boc); 2.98-3.12 (m, 4H, 2 (CH₂)_(β)); 4.47 (m, 1H,(CH)α_(A&B)); 5.2 (m, 0.4H, (CH)α′_(B)); 5.7 (m, 0.6H, (CH)α′_(A));6.95-8.37 (m, 15H, 2 indoles (10H), 3 NH (amides), 1 NH (urethane), CHO(formyl)); 10.89 (m, 2H, 2 N¹H (indoles)). Mass Spectrometry(Electrospray), m/z 575 [M+H]⁺, 597 [M+Na]⁺, 1149 [2M+H]⁺, 1171[2M+Na]⁺.

H-Aib-D-Trp-D-gTrp-CHO

Boc-Aib-D-Trp-D-gTrp-CHO (1 g; 1.7 mmol) was dissolved in a mixture oftrifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole (1 ml) for30 minutes at 0° C. The solvents were removed in vacuo, the residue wasstirred with ether and the precipitated TFA, H-Aib-D-Trp-D-gTrp-CHO wasfiltered.

The product TFA, H-Aib-D-Trp-D-gTrp-CHO was purified by preparative HPLC(Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).

Yield=52%. C₂₆H₃₀N₆O₃, 474 g·mol⁻¹. ¹H NMR (400 MHZ, DMSO-d⁶)+¹H/¹Hcorrelation: δ 1.21 (s, 3H, CH₃ (Aib)); 1.43 (s, 3H, CH₃ (Aib)); 2.97(m, 2H, (CH₂)_(β)); 3.1 (m, 2H, (CH₂)_(β)); 4.62 (m, 1H, (CH)α_(A&B));5.32 (q, 0.4H, (CH)α′_(B)); 5.71 (q, 0.6H, (CH)α′_(A)); 7.3 (m, 4H, H₅and H₆ (2 indoles)); 7.06-7.2 (4d, 2H, H_(2A) et H_(2B) (2 indoles));7.3 (m, 2H, H₄ or H₇ (2 indoles)); 7.6-7.8 (4d, 2H, H_(4A) H_(7A) etH_(7B)); 7.97 (s, 3H, NH₂ (Aib) and CHO (Formyl)); 8.2 (d, 0.4H, NH_(1B)(diamino)); 8.3 (m, 2H, NH_(A&B)); 8.5 (d, 0.6H, NH_(1A) (diamino));8.69 (d, 0.6H, NH_(2A) (diamino)); 8.96 (d, 0.4H, NH_(2B) (diamino));10.8 (s, 0.6H, N¹H_(1A) (indole)); 10.82 (s, 0.4H, N¹H_(1B) (indole));10.86 (s, 0.6H, N¹H_(2A) (indole)); 10.91 (s, 0,4H, N¹H_(2B) (indole)).Mass Spectrometry (Electrospray), m/z 475 [M+H]⁺, 949 [2M+H]⁺.

Analogous synthesis were performed for the following compounds:

Example 2 H-Aib-D-Mrp-D-gMrp-CHO

C₂₈H₃₄N₆O₃, 502 g·mol⁻¹. ¹H NMR (400 MHZ, DMSO-d⁶)+¹H/¹H correlation: δ1.19 (s, 2H, (CH₃)_(1A) (Aib)); 1.23 (s, 1H, (CH₃)_(1B) (Aib)); 1.41 (s,2H, (CH₃)_(2A) (Aib)); 1.44 (s, 2H, (CH₃)_(2B) (Aib)); 2.33-2.35 (4s,6H, 2 CH₃ (indoles)); 2.93 (m, 2H, (CH₂)_(β)); 3.02 (m, 2H, (CH₂)_(β));4.65 (m, 0.6H, (CH)α_(A)); 4.71 (m, 0.4H, (CH)α_(B)); 5.2 (m, 0.4H,(CH)α′_(B)); 5.6 (m, 0.6H, (CH)α′_(A)); 6.95 (m, 4H, H₅ and H₆ (2indoles)); 7.19 (m, 2H, H₄ or H₇ (2 indoles)); 7.6 (m, 2H, H₄ or H₇ (2indoles)); 7.9 (s, 1H, CHO (Formyl)); 7.95 (s, 2H, NH₂ (Aib)); 8.05 (d,0.4H, NH_(1B) (diamino)); 8.3 (m, 1H, NH_(A&B)); 8.35 (m, 0.6H, NH_(1A)(diamino)); 8.4 (d, 0.6H, NH_(2A) (diamino)); 8.75 (d, 0.4H, NH_(2B)(diamino)); 10.69 (s, 0.6H, N¹H_(1A) (indole)); 10.71 (s, 0.4H, N¹H_(1B)(indole)); 10.80 (s, 0.6H, N¹H_(2A) (indole)); 10.92 (s, 0.4H, N¹H_(2B)(indole)). Mass Spectrometry (Electrospray), m/z 503.1 [M+H]⁺.

Example 3 N-Me-Aib-D-Trp-D-gTrp-CHO

Boc-N-Me-Aib-OH (327 mg; 1.5 mmol; 2.6 eq.) was dissolved in methylenechloride (10 ml) and cooled to 0° C. Then, dicyclohexylcarbodiimide (156mg; 0.75 mmol; 1.3 eq.) was added. The mixture, after filtration of DCU,was added to a solution containing TFA, H-D-Trp-D-gTrp-CHO (0.58 mmol; 1eq.) and triethylamine (267 μl; 3.3 eq.) in methylene chloride (5 ml).The reaction mixture was slowly warmed to room temperature and stoppedafter 24 hr. The mixture was diluted with ethyl acetate (25 ml) andwashed with saturated aqueous sodium hydrogen carbonate (50 ml), aqueouspotassium hydrogen sulfate (50 ml, 1M), and saturated aqueous sodiumchloride (50 ml). The organic layer was dried over sodium sulfate,filtered and the solvent removed in vacuo. The residue was purified byflash chromatography on silica gel eluting with ethyl acetate/methanol{9/1} to afford 180 mg (53%) of Boc-N-Me-Aib-D-Trp-D-gTrp-CHO as a whitefoam.

Boc-N-Me-Aib-D-Trp-D-gTrp-CHO (180 mg; 0.3 mmol) was dissolved in amixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole(1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, theresidue was stirred with ether and the precipitated TFA,N-Me-Aib-D-Trp-D-gTrp-CHO was filtered.

The product TFA, N-Me-Aib-D-Trp-D-gTrp-CHO (39 mg; 15%) was purified bypreparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).

C₂₇H₃₂N₆O₃, 488 g·mol⁻¹. ¹H RMN (200 MHZ, DMSO-d⁶): δ 1.19 (s, 3H, CH₃(Aib)); 1.42 (s, 3H, CH₃ (Aib)); 2.26 (s, 3H, NCH₃); 3.12 (m, 4H, 2(CH₂)_(β)); 4.66 (m, 1H, (CH)_(α)); 5.32 et 5.7 (m, 1H, (CH)_(α′));6.9-7.8 (m, 10H, 2 indoles); 8 (m, 1H, CHO (formyl)); 8.2-9 (m, 4H, 3 NH(amides) et NH (amine)); 10.87 (m, 2H, 2 N¹H (indoles)). MassSpectrometry (Electrospray), m/z 489.29 [M+H]⁺.

Example 4 H-Aib-D-Trp-D-gTrp-C(O)CH₃

Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-H (0.72 mmol; 1 eq.) was dissolvedin DMF (20 ml). Then, N,N-diisopropylethylamine (259 ml; 2.1 eq.) andacetic anhydride (749 ml; 1.1 eq.) were added. After 1 hr, the mixturewas diluted with ethyl acetate (100 ml) and washed with saturatedaqueous sodium hydrogen carbonate (100 ml), aqueous potassium hydrogensulfate (100 ml, 1M), and saturated aqueous sodium chloride (50 ml). Theorganic layer was dried over sodium sulfate, filtered and the solventremoved in vacuo. The residue was purified by flash chromatography onsilica gel eluting with ethyl acetatethexane to afford 370 mg (73%) ofBoc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-C(O)CH₃ as a white solid.

Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-C(O)CH₃ (350 mg; 0.5 mmol; 1 eq.)was dissolved in a mixture of trifluoroacetic acid (8 ml), anisole (1ml) and thioanisole (1 ml) for 30 minutes at 0° C. The solvents wereremoved in vacuo, the residue was stirred with ether and theprecipitated TFA, H-D-Trp-D-gTrp-C(O)CH₃ was filtered.

In 10 ml of DMF, TFA, H-D-Trp-D-gTrp-C(Q)CH₃ (0.5 mmol; 1 eq.),Boc-Aib-OH (121 mg; 0.59 mmol; 1.2 eq.), NMM (230 μl; 4.2 eq.) and BOP(265 mg; 1.2 eq.) were successively added. After 1 hr, the mixture wasdiluted with ethyl acetate (25 ml) and washed with saturated aqueoussodium hydrogen carbonate (50 ml), aqueous potassium hydrogen sulfate(50 ml, 1M), and saturated aqueous sodium chloride (50 ml). The organiclayer was dried over sodium sulfate, filtered and the solvent removed invacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate to afford 249 mg (85%) ofBoc-Aib-D-Trp-D-gTrp-C(O)CH₃ as a white foam.

Boc-Aib-D-Trp-D-gTrp-C(O)CH₃ (249 mg; 0.42 mmol) was dissolved in amixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole(1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, theresidue was stirred with ether and the precipitated TFA,H-Aib-D-Trp-D-gTrp-C(O)CH₃ was filtered.

The product TFA, H-Aib-D-Trp-D-gTrp-C(O)CH₃ (80 mg; 23%) was purified bypreparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 mm, 100 A).

C₂₇H₃₂N₆O₃, 488 g·mol⁻¹. ¹H NMR (200 MHZ, DMSO-d⁶): δ 1.22 (s, 3H, CH₃(Aib)); 1.44 (s, 3H, CH₃ (Aib)); 1.8 (s, 3H, C(O)CH₃); 3.06 (m, 4H, 2(CH₂)_(β)); 4.6 (m, 1H, (CH)_(α)); 5.6 (m, 1H, (CH)_(α′)); 6.9-7.8 (m,10H, 2 indoles); 7.99 (s, 2H, NH₂ (Aib)); 8.2-8.6 (m, 3H, 3 NH(amides)); 10.83 (s, 2H, 2 N¹H (indoles)). Mass Spectrometry(Electrospray), m/z 489.32 [M+H]⁺.

Example 5 N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃

Boc-N-Me-Aib-OH (1.09 g; 5.04 mmol; 4 eq.) was dissolved in methylenechloride (10 ml) and cooled to 0° C. Then, dicyclohexylcarbodiimide (520mg; 2.52 mmol; 2 eq.) was added. The mixture, after filtration of DCU,was added to a solution containing TFA, H-D-Trp-D-gTrp-C(O)CH₃ (940 mg;1.26 mmol; 1 eq.) and triethylamine (580 ml; 3.3 eq.) in methylenechloride (5 ml). The reaction mixture was slowly warmed to roomtemperature and stopped after 24 h. The mixture was diluted with ethylacetate (50 ml) and washed with saturated aqueous sodium hydrogencarbonate (100 ml), aqueous potassium hydrogen sulfate (100 ml, 1M), andsaturated aqueous sodium chloride (100 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/methanol {9/1} to afford 530 mg (70%) ofBoc-N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃ as a white foam.

Boc-N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃ (530 mg; 0.88 mmol) was dissolved in amixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole(1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, theresidue was stirred with ether and the precipitated TFA,N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃ was filtered.

The product TFA, N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃ (220 mg; 30%) waspurified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 mm,100 A).

C₂₆H₃₄N₆O₃, 502 g·mol⁻¹. ¹H NMR (200 MHZ, DMSO-d⁶): δ 1.17 (s, 3H, CH₃(Aib)); 1.4 (s, 3H, CH₃ (Aib)); 1.78 (s, 3H, C(O)CH₃); 2.23 (s, 3H,NCH₃); 3.15 (m, 4H, 2 (CH₂)_(β)); 4.7 (m, 1H, (CH_(α)); 5.55 (m, 1H,(CH)_(α′)); 6.9-7.9 (m, 10H, 2 indoles); 8.2-8.8 (s, 4H, NH (amine) et 3NH (amides)); 10.8 (s, 2H, 2 N¹H (indoles)). Mass Spectrometry(Electrospray), m/z 503.19 [M+H]⁺.

Example 6 Pip-D-Trp-D-gTrp-CHO

In 5 ml of DMF, TFA, H-D-Trp-D-gTrp-CHO (230 mg; 0.31 mmol; 1 eq.),Boc-(N⁴Boc)Pip-OH (130 mg; 0.38 mmol; 1.2 eq.), NMM (145 μl; 4.2 eq.)and BOP (167 mg; 0.38 mmol; 1.2 eq.) were successively added. After 15minutes, the reaction was over. The mixture was diluted with ethylacetate (25 ml) and washed with saturated aqueous sodium hydrogencarbonate (50 ml), aqueous potassium hydrogen sulfate (50 ml, 1M), andsaturated aqueous sodium chloride (50 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo to affordBoc-(N⁴Boc)Pip-D-Trp-D-gTrp-CHO as a foam.

Boc-(N⁴Boc)Pip-D-Trp-D-gTrp-CHO (0.31 mmol) was dissolved in a mixtureof trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole (1 ml)for 30 minutes at 0° C. The solvents were removed in vacuo, the residuewas stirred with ether and TFA, H-Pip-D-Trp-D-gTrp-CHO was filtered.

The product TFA, H-Pip-D-Trp-D-gTrp-CHO (127 mg; 42%) was purified bypreparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).

C₂₈H₃₃N₇O₃, 515 g·mol⁻¹. ¹H RMN (200 MHZ, DMSO-d⁶): δ 1.81 (m, 2H, CH₂(Pip)); 2.3 (m, 2H, CH₂ (Pip)); 3.1 (m, 8H, 2 (CH₂)_(β) et 2 CH₂ (Pip));4.68 (m, 1H, (CH)_(α)); 5.3 et 5.73 (2 m, 1H, (CH)_(α′)); 6.9-7.7 (m,10H, 2 indoles); 7.98 (2s, 1H, CHO (formyl)); 8.2-9.2 (m, 6H, NH₂ et NH(Pip) et 3 NH (amides)); 10.9 (m, 2H, 2 N¹H (indoles)). MassSpectrometry (Electrospray), m/z 516.37 [M+H]⁺, 538.27 [M+Na]⁺.

Example 7 Pip-D-Trp-D-gTrp-C(O)CH₃

In 5 ml of DMF, TFA, H-D-Trp-D-gTrp-C(O)CH₃ (218 mg, 0.29 mmol; 1 eq.),Boc-(N⁴Boc)Pip-OH (121 mg; 0.35 mmol; 1.2 eq.), NMM (135 μl; 4.2 eq.)and BOP (155 mg; 0.35 mmol; 1.2 eq.) were successively added. After 15minutes, the reaction was over. The mixture was diluted with ethylacetate (25 ml) and washed with saturated aqueous sodium hydrogencarbonate (50 ml), aqueous potassium hydrogen sulfate (50 ml, 1M), andsaturated aqueous sodium chloride (50 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo to affordBoc-(N⁴Boc)Pip-D-Trp-D-gTrp-C(O)CH³ as a foam.

Boc-(N⁴Boc)Pip-D-Trp-D-gTrp-C(O)CH₃ (0.29 mmol) was dissolved in amixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole(1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, theresidue was stirred with ether and the precipitated TFA,H-Pip-D-Trp-D-gTrp-C(O)CH₃ was filtered.

The product TFA, H-Pip-D-Trp-D-gTrp-C(O)CH₃ (135 mg; 47%) was purifiedby preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).

C₂₉H₃₅N₇O₃, 529 g·mol⁻¹. ¹H RMN (200 MHZ, DMSO-d⁶): δ 1.79 (m, 2H, CH₂(Pip)); 1.81 (s, 3H, C(O)CH₃); 2.3 (m, 2H, CH₂ (Pip)); 3.1 (m, 8H, 2(CH₂)_(β) et 2 CH₂ (Pip)); 4.7 (m, 1H, (CH)α); 5.6 (m, 1H, (CH)_(α′));6.9-7.8 (m, 10H, 2 indoles); 8.2-9 (m, 6H, NH₂ et NH (Pip) et 3 NH(amides)); 10.85 (m, 2H, 2 N¹H (indoles)). Mass Spectrometry(Electrospray), m/z 530.39 [M+H]⁺, 552.41 [M+Na]⁺.

Example 8 Isonipecotyl-D-Trp-D-gTrp-CHO

In 5 ml of DMF, TFA, H-D-Trp-D-gTrp-CHO (250 mg, 4.1 mmol; 1 eq.),Fmoc-Isonipecotic-OH (144 mg; 4.1 mmol; 1.2 eq.), NMM (158 μl; 4.2 eq.)and BOP (181 mg; 4.1 mmol; 1.2 eq.) were successively added. After 15minutes, the reaction was over. The mixture was diluted with ethylacetate (25 ml) and washed with saturated aqueous sodium hydrogencarbonate (50 ml), aqueous potassium hydrogen sulfate (50 ml, 1M), andsaturated aqueous sodium chloride (50 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo to affordFmoc-Isonipecotyl-D-Trp-D-gTrp-CHO as a foam.

Fmoc-Isonipecotyl-D-Trp-D-gTrp-CHO (4.1 mmol) was dissolved in a mixtureof DMF (8 ml) and piperidine (2 ml) and allowed to stand for 30 minutes.The solvents were removed in vacuo, the residue was stirred with etherand the precipitated Isonipecotyl-D-Trp-D-gTrp-CHO was filtered.

The product Isonipecotyl-D-Trp-D-gTrp-CHO (81 mg; 28%) was purified bypreparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).

C₂₈H₃₂N₆O₃, 500 g·mol⁻¹. ¹H RMN (200 MHZ, DMSO-d⁶): δ 1.65 (m, 4H, 2 CH₂(Pip)); 2.4 (m, 1H, CH (Pip)); 2.7-3.3 (m, 8H, 2 (CH₂)_(β) et 2 CH₂(Pip)); 4.6 (m, 1H, (CH)_(α)); 5.3 et 5.7 (2 m, 1H, (CH)_(α′)); 6.9-7.7(m, 10H, 2 indoles); 7.97 (2s, 1H, CHO (formyl)); 8-8.8 (m, 4H, NH (Pip)et 3 NH (amides)); 10.9 (m, 2H, 2 N¹H (indoles)). Mass Spectrometry(Electrospray), m/z 501.36 [M+H]⁺.

Example 9 Isonipecotyl-D-Trp-D-gTrp-C(O)CH₃

In 5 ml of DMF, TFA, H-D-Trp-D-gTrp-C(O)CH₃ (250 mg, 0.33 mmol; 1 eq.),Fmoc-Isonipecotic-OH (141 mg; 0.4 mmol; 1.2 eq.), NMM (155 μl; 4.2 eq.)and BOP (178 mg; 0.4 mmol; 1.2 eq.) were successively added. After 15minutes, the reaction was over. The mixture was diluted with ethylacetate (25 ml) and washed with saturated aqueous sodium hydrogencarbonate (50 ml), aqueous potassium hydrogen sulfate (50 ml, 1M), andsaturated aqueous sodium chloride (50 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo to affordFmoc-Isonipecotyl-D-Trp-D-gTrp-C(O)CH₃ as a foam.

Fmoc-Isonipecotyl-D-Trp-D-gTrp-C(O)CH₃ (0.33 mmol) was dissolved in amixture of DMF (8 ml) and piperidine (2 ml) and allowed to stand for 30minutes. The solvents were removed in vacuo, the residue was stirredwith ether and the precipitated Isonipecotyl-D-Trp-D-gTrp-C(O)CH₃ wasfiltered.

The product Isonipecotyl-D-Trp-D-gTrp-C(O)CH3 (65 mg; 13%) was purifiedby preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).

C₂₉H₃₄N₆O₃, 514 g·mol⁻¹. ¹H RMN (200 MHZ, DMSO-d⁶): δ 1.66 (m, 4H, 2 CH₂(Pip)); 1.79 (s, 3H, C(O)CH₃); 2.7-3.3 (m, 8H, 2 (CH₂)_(β) et 2 CH₂(Pip)); 4.54 (m, 1H, (CH)_(α)); 5.59 (m, 1H, (CH)_(α′)); 6.9-7.7 (m,10H, 2 indoles); 8-8.6 (m, 4H, NH (Pip) et 3 NH (amides)); 10.82 (m, 2H,2 N¹H (indoles)). Mass Spectrometry (Electrospray), m/z 515.44 [M+H]⁺.

Examples 10-62

The following compounds were prepared in similar manners:

Example 10 H-Aib-D-Mrp-gMrp-CHO Example 11 H-Aib-Trp-gTrp-CHO Example 12H-Aib-Trp-D-gTrp-CHO Example 13 H-D-Trp-gTrp-CHO Example 14N-Me-D-Trp-gTrp-CHO Example 15 N-Methylsulfonyl-D-Trp-gTrp-CHO Example16 N-Phenylsulfonyl-D-Trp-gTrp-CHO Example 17N-(3-Methyl-butanoyl)-D-Trp-gTrp-CO—CH₃ Example 18N-(3-Methyl-butanoyl)-D-Trp-gTrp-CHO Example 19Aib-D-Trp-gTrp-CO—CH₂—CH₃ Example 20 Aib-D-Trp-gTrp-CO—CH₂—CH(CH₃)—CH₃Example 21 Aib-D-Trp-gTrp-CO—CH₂-phenyl Example 22Aib-D-Trp-gTrp-CO-piperidin-4-yl Example 23Aib-D-Trp-gTrp-CO—CH₂-pyrrol-3-yl Example 24Aib-D-Trp-gTrp-CO—CH₂—CH₂-cyclohexyl Example 25N-Me-Aib-D-Trp-gTrp-CO—CH₂—CH₃ Example 26N-Me-Aib-D-Tip-gTrp-CO—CH₂—CH(CH₃)—CH₃ Example 27N-Me-Aib-D-Trp-gTrp-CO—CH₂-phenyl Example 28N-Me-Aib-D-Trp-gTrp-CO—CH₂-pyrrol-3-yl Example 29N-Me-Aib-D-Trp-gTrp-CO—CH₂—CH₂-cyclohexyl Example 30 Aib-D-Trp-gTrp-CHOExample 31 N-(3-amino-3-methyl-butanoyl)-D-Trp-gTrp-CO—CH₃ Example 32N-Acetyl-D-Trp-gTrp-CHO Example 33 N-Acetyl-D-Trp-gTrp-CO—CH₃ Example 34N-Formyl-D-Trp-gTrp-CHO Example 35 N-Formyl-D-Trp-gTrp-CO—CH₃ Example 36N-(1,1-dimethyl-2-amino-2-keto-ethyl)-D-Trp-gTrp-CHO Example 37N-(2-amino-2-methyl-propyl)-D-Trp-gTrp-CHO Example 38N-(2-amino-2-methyl-propyl)-D-Trp-gTrp-CO—CH₃ Example 39N-Me-Aib-D-Trp-D-gTrp-Isonipecotyl Example 40N-Me-Aib-D-Trp-N-Me-D-gTrp-C(O)CH₃ Example 41H-Aib-D-Trp-N-Me-D-gTrp-C(O)CH₃ Example 42H-Aib-(D)-1-Nal-g-(D)-1-Nal-formyl

C₃₀H₃₂N₄O₃, 496 g·mol⁻. ¹H RMN (200 MHz, DMSO-d⁶): δ 1.14 and 1.4 (2 m,6H, 2 CH₃ (Aib)); 3.17-3.55 (m, 4H, 2 (CH₂)_(β)); 4.82 (m, 1H, CHα); 5.5and 5.82 (2 m, 1H, CHα); 7.36-7.64 (m, 8H); 7.83-8 (m, 7H); 8.25-9.45(m, 5H). Mass Spectrometry (FAB), m/z 497 [M+H]⁺. Analytic HPLC (DeltaPak 5μ C18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN 0.1% TFA, gradient 0to 100% ACN in 50 min), tr=20.28 min, 99%. Freezedried Compound.

Example 43 H-Aib-(D)-2-Nal-g-(D)-2-Nal-formyl

C₃₀H₃₂N₄O₃, 496 g·mol⁻¹. ¹H RMN (200 MHz, DMSO-d⁶): δ 1.18 and 1.36 (2m, 6H, 2 CH₃ (Aib)); 2.84-3.3 (m, 4H, 2 (CH₂)_(β)); 4.7 (m, 1H, CHα);5.45 and 5.73 (2 m, 1H, CHα); 7.47-7.51 (m, 6H); 7.76-8.06 (m, 11H);8.36-9.11 (m, 3H). Mass Spectrometry (FAB), m/z 497 [M+H]⁺. AnalyticHPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN 0.1% TFA,gradient 0 to 100% ACN in 50 min), tr=20.26 mm, 95%. FreezedriedCompound.

Example 44 H-Aib-(D)-1-Nal-g-(D)-Trp-formyl

C₂₈H₃₁N₅O₃, 485 g·mol⁻¹. ¹H RMN (200 MHz, DMSO-d⁶): δ 1.15 and 1.42 (2m, 6H, 2 CH₃ (Aib)); 3.11-3.3 and 3.54-3.7 (m, 4H, 2 (CH₂)_(β)); 4.81(m, 1H, CH_(α)); 5.4 and 5.74 (2 m, 1H, CH_(α′)); 7.06-7.2 (m, 3H);7.34-7.65 (m, 6H); 7.91-8.1 (m, 4H); 8.2-8.4 (m, 1H); 8.55-9.5 (m, 3H);10.95 (m, 1H, N¹H). Mass Spectrometry (FAB), m/z 486 [M+H]⁺. AnalyticHPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN 0.1% TFA,gradient 0 to 100% ACN in 50 min), tr=17.33 mm, 92%. FreezedriedCompound.

Example 45 H-Aib-(D)-2-Nal-g-(D)-Trp-formyl

C₂₈H₃₁N₅O₃, 485 g·mol⁻¹. ¹H RMN (200 MHz, DMSO-d⁶): δ 1.19 and 1.45 (2m, 6H, 2 CH₃ (Aib)); 2.93-3.3 (m, 4H, 2 (CH₂)_(β)); 4.71 (m, 1H,CH_(α)); 5.35 and 5.7 (2 m, 1H, CH_(α′)); 7.05-7.1 (m, 2H); 7.2-7.34 (m,1H); 7.47-7.53 (m, 4H); 7.64 (m, 1H); 7.78-8 (m, 8H); 8.48-9.37 (m, 2H);10.88-11.04 (m, 1H, N¹H). Mass Spectrometry (FAB), m/z 486 [M+H]⁺.Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=17.30 min, 95%.Freezedried Compound.

Example 46 H-Aib-(D)-Trp-g-(D)-1-Nal-formyl

C₂₈H₃₁N₅O₃, 485 g·mol⁻¹. ¹H RMN (200 MHz, DMSO-d⁶): δ 1.23 and 1.41 (2m, 6H, 2 CH₃ (Aib)); 2.92-3.15 (m, 2H, (CH₂)_(β)); 3.4-3.6 (m, 2H,(CH₂)_(β)); 4.63 (m, 1H, CH_(α′)); 5.44 and 5.79 (2 m, 1H, CH_(α′));6.99-7.15 (m, 3H); 7.33 (m, 1H); 7.45-8.1 (m, 11H); 8.34-9.37 (m, 3H);10.83 (m, 1H). Mass Spectrometry (FAB), m/z 486 [M+H]⁺. Analytic HPLC(Symmetry shield 3.5μ C18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN 0.1%TFA, gradient 0 to 60% ACN in 15 min then 60 to 100% ACN in 3 min),tr=10.00 min, 99%. Freezedried Compound.

Example 47 H-Aib-D-Trp-g-D-2-Nal-formyl

C₂₈H₃₁N₅O₃, 485 g·mol⁻¹. ¹H RMN (200 MHz, DMSO-d⁶): δ 1.22 and 1.43 (2m, 6H, 2 CH₃ (Aib)); 2.85-3.3 (m, 4H, 2 (CH₂)_(β)); 4.64 (m, 1H,CH_(α)); 5.37 and 5.72 (2 m, 1H, CH_(α′)); 6.97-7.13 (m, 3H); 7.32 (m,1H); 7.44-7.54 (m, 3H); 7.66 (d, 1H); 7.78 (m, 1H); 7.86-8.02 (m, 7H);8.33-9.4 (m, 2H); 10.82 (m, 1H, N¹H). Mass Spectrometry (FAB), m/z 486[M+H]⁺. Analytic HPLC (Delta pak 5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 25 min), tr=9.00 min, 99%.Freezedried Compound.

Example 48 H-Aib-(D)-Trp-g-(D)-3-(R/S)Dht-formyl

C₂₆H₃₂N₆O₃, 476 g·mol⁻¹. ¹H RMN (400 MHz, DMSO-d⁶): δ 1.12 (s, 3H, CH₃(Aib)); 1.32 (s, 3H, CH₃ (Aib)); 1.73 (m, 1H, CH₂); 2.01 (m, 1H, CH₂);2.9 (m, 1H); 3.03 (m, 1H); 3.13 (m, 2H); 3.54 (m, 1H); 4.47 (m, 1H,CH_(α)); 5.10 and 5.52 (2 m, 1H, CH_(α′)); 6.71-8.83 (m, 16H, 5H (Trp),4H (Dht), 3 NH (amides), NH and NH₂ (amines), formyl); 10.7 (m, 1H,N¹H). Mass Spectrometry (Electrospray), m/z 477.46 [M+H]⁺ 499.42[M+Na]⁺; 953.51 [2M+H]⁺. Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min,214 nm, eluent: H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min),tr=9.40 min, 98%. Freezedried Compound.

Example 49 H-Aib-(D)-3(R/S)Dht-g-(D)-Trp-formyl

C₂₆H₃₂N₆O₃, 476 g·mol⁻¹. RMN ¹H(400 MHz, DMSO-d⁶): δ 1.58 (s, 3H, CH₃(Aib)); 1.85 (m, 1H, CH₂); 2.2 (m, 1H, CH₂); 3;1 (d, 2H); 3.35 (m, 2H);3.56 (m, 1H); 3.7 (m, 1H); 4.5 (m, 1H, CH_(α)); 5.33 and 5.71 (2 m, 1H,CH_(α′)); 6.88-8.91 (m, 16H, 5H (Trp), 4H (Dht), 3 NH (amides), NH andNH₂ (amines), formyl); 10.92 and 10.97 (2s, 1H, N¹H). Mass Spectrometry(Electrospray), m/z 477.33 [M+I]⁺; 499.42 [M+Na]⁺ 953.51 [2M+H]⁺.Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=10.35 mm, 98%.Freezedried Compound.

Example 50 N-Me-Aib-(D)-Trp-g-(D)-3(R/S)Dht-acetyl

C₂₈H₃₆N₆O₃, 504 g·mol⁻¹. ¹H RMN (400 MHz, DMSO-d⁶): δ 1.42 (s, 3H, CH₃(Aib)); 1.63 (s, 3H, CH₃ (Aib)); 2.72 (m, 3H, acetyl); 2.4 (m, 2H, CH₂);2.5 (m, 3H, NCH₃); 3.2-3.5 (m, 4H); 3.85 (m, 1H); 4.85 (m, 1H, CH_(α));5.76 (m, 1H, CH_(α′)); 7.04-8.86 (m, 14H, 5H (Trp), 4H (Dht), 3 NH(amides), 2 NH (amines)); 11.02 (2s, 1H, N¹H). Mass Spectrometry(Electrospray), m/z 505,31 [M+H]⁺; 527,70 [M+Na]⁺. Analytic HPLC (DeltaPak 5μ C18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN 0.1% TFA, gradient 0to 100% ACN in 50 min), tr=10.20 min, 98%. Freezedried Compound.

Example 51 N-Me-Aib-(D)-3(RS)Dht-g-(D)-Trp-acetyl

C₂₈H₃₆N₆O₃, 504 g·mol⁻¹. ¹H RMN (400 MHz, DMSO-d⁶): δ 1.58 (s, 6H, 2 CH₃(Aib)); 1.81 (m, 3H, acetyl); 1.98 (m, 1H, CH₂); 2.24 (m, 1H, CH₂); 2.54(m, 3H, NCH₃); 3.08 (d, 2H); 3.31 (m, 2H); 3.4 (m, 1H); 3.59 (m, 1H);3.71 (m, 1H); 4.52 (m, 1H, CH_(α′)); 5.61 (m, 1H, CH_(α′)); 6.9-8.92 (m,14H, 5H (Trp), 4H (Dht), 3 NH (amides), 2 NH (amines)); 10.88 (s, 1H,N¹H). Mass Spectrometry (Electrospray), m/z 505.43 [M+H]⁺; 527.52[M+Na]⁺. Analytic HPLC (Delta Pak 5μ C18100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=11 min, 98%.Freezedried Compound.

Example 52 N(Me)₂-Aib-(D)-Trp-(D)-gTrp-formyl

C₂₈H₃₆N₆O₃, 502 g·mol⁻¹. ¹H RMN (400 MHz, DMSO-d⁶): δ 1.2 (s, 3H, CH₃(Aib)); 1.39 (s, 3H, CH₃ (Aib)); 2.29 (m, 3H, NCH₃); 2.99-3.33 (m, 4H, 2(CH₂)_(β)); 4.68 (m, 1H, CH)_(α)); 5.3 and 5.69 (m, 1H, CH)_(α′));6.97-7.72 (m, 10H, 2 indoles); 7.97 (2s, 1H, formyl); 8.2-9.47 (m, 3H, 3NH (amides)); 10.85 (m, 2H, 2 NH (indoles)). Mass Spectrometry(Electrospray), m/z 503.45 [M+H]⁺. Analytic HPLC (Symmetry shield 3.5μC18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN 0.1% TFA, gradient 0 to 100%ACN in 15 min), tr=6.63 min, 99%. Freezedried Compound.

Example 53 N(Me)₂-Aib-D-Trp-D-gTrp-acetyl

C₂₉H₃₆N₆O₃, 516 g·mol⁻¹. ¹H RMN (200 MHz, DMSO-d⁶): δ 1.22 (s, 3H, CH₃(Aib)); 1.4 (s, 3H, CH₃ (Aib)); 1.8 (s, 3H, acetyl); 2.28 (d, 3H, NCH₃);2.96-3.22 (m, 4H, 2 (CH₂)_(β)); 4.7 (m, 1H, CH_(α)); 5.60 (m, 1H,(CH)_(α′)); 6.98-7.75 (m, 10H, 2 indoles); 8.2-9.47 (m, 3H, 3 NH(amides)); 10.84 (m, 2H, 2 NH (indoles)). Mass Spectrometry(Electrospray), m/z 517.34 [M+H]⁺. Analytic HPLC (Symmetry shield 3.5μC18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN 0.1% TFA, gradient 0 to 100%ACN in 15 min), tr=7.07 mm, 99%. Freezedried Compound.

Example 54 H-Acc³-(D)-Trp-(D)-gTrp-formyl

C₂₆H₂₈N₆O₃, 472 g·mol⁻¹. ¹H RMN (400 MHz, DMSO-d⁶): δ 1.11 and 1.5 (2 m,4H, 2 CH₂ (Acc³)); 2.91-3.12 (m, 4H, 2 (CH₂)_(β)); 4.6 (m, 1H, CH_(α));5.3 and 5.7 (2 m, 1H, CH_(α′)); 6.97-7.17 (m, 6H, indoles); 7.32 (m, 2H,indoles); 7.62-7.72 (m, 2H, indoles); 7.97 (2s, 1H, formyl); 8.27-8.92(m, 5H, 3 NH (amides) and NH₂ (amine)); 10.80-10.90 (4s, 2H, 2 N¹H).Mass Spectrometry (Electrospray), m/z 473.22 [M+H]⁺; 495.15 [M+Na]⁺945.47 [2M+H]⁺; 967.32 [2M+Na]⁺. Analytic HPLC (Delta Pak 5μ C18 100A, 1ml/min, 214 nm, eluent: H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50min), tr=14.20 min, 98%. Freezedried Compound.

Example 55 H-Acc⁵-(D)-Trp-(D)-gTrp-formyl

C₂₆H₂₈N₆O₃, 472 g·mol⁻¹. ¹H RMN (400 MHz, DMSO-d⁶): δ 1.51 and 2.31 (m,8H, 4 CH₂ (Acc⁵)); 2.97-3.18 (m, 4H, 2 (CH₂)_(β)); 4.64 (m, 1H, CH_(α));5.31 and 5.69 (2 m, 1H, CH_(α′)); 6.96-7.34 (m, 8H, indoles); 7.62-7.74(m, 2H, indoles); 7.96 (m, 3H, formyl and NH₂ (amine)); 8.48-8.96 (m,3H, 3 NH (amides); 10.80-10.90 (4s, 2H, 2 N¹H). Mass Spectrometry(Electrospray), m/z 501.31 [M+H]⁺; 523.42 [M+Na]⁺; 101.37 [2M+H]⁺.Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=15.35 min, 98%.Freezedried Compound.

Example 56 H-Acc⁶-(D)-Trp-(D)-gTrp-formyl

C₂₆H₂₈N₆O₃, 472 g·mol⁻¹. ¹H RMN (400 MHz, DMSO-d⁶): δ 1.29-1.57 (m, 8H,4 CH₂ (Acc⁶)); 1.89 and 2.04 (2 m, 2H, CH₂ (Acc⁶)); 2.95-3.17 (m, 4H, 2(CH₂)_(β)); 4.61 (m, 1H, CH_(α)); 5.3 and 5.68 (2 m, 1H, CH_(α′));6.95-7.21 (m, 6H, indoles); 7.32 (m, 2H, indoles); 7.6 (m, 2H, indoles);7.74 (m, 2H, indoles); 7.96 (m, 3H, formyl and NH₂ (amine)); 8.18-8.67(m, 5H, 3 NH (amides)); 10.77-10.89 (4s, 2H, 2N¹H). Mass Spectrometry(Electrospray), m/z 515.11 [M+H]⁺. Analytic HPLC (Delta Pak 5μ C18 100A,1 ml/min, 214 nm, eluent: H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50min), tr=15.9 min, 97%. Freezedried Compound.

Example 57 H-Dpg-(D)-Trp-(D)-gTrp-formyl

C₂₆H₂₈N₆O₃, 530 g·mol⁻¹. ¹H RMN (400 MHz, DMSO-d⁶): δ 0 (m, 1H, Dpg);0.40 (m, 3H, Dpg); 0.70 (m, 4H, Dpg); 1.01-1.51 (m, 5H, Dpg); 1.76 (m,1H, Dpg); 2.82-2.95 (m, 4H, 2 (CH₂)_(β)); 4.59 (m, 1H, CH_(α)); 5.3 and5.54 (2 m, 1H, CH_(α′)); 6.81-7.09 (m, 6H, indoles); 7.19 (m, 2H,indoles); 7.48 (m, 1H, indoles); 7.6-7.68 (m, 5H, 1H (indoles), formyland NH₂ (amine); 7.83-8.82 (m, 3H, 3 NH (amides)); 10.69 and 10.76 (2 m,2H, 2N¹H). Mass Spectrometry (Electrospray), m/z 531.24 [M+I]⁺. AnalyticHPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN 0.1% TFA,gradient 0 to 100% ACN in 50 mm), tr=15.35 mm, 98%. FreezedriedCompound.

Example 58 H-Aib-(D)-Trp-(D)-gTrp-C(O)NHCH₂CH₃

C₂₆H₂₅N₇O₃, 517 g·mol⁻¹. ¹H RMN (400 MHz, DMSO-d⁶): δ 0.94 (t, 3H,NHCH₂CH ₃); 1.01 (s, 3H, CH₃ (Aib)); 1.08 (s, 3H, CH₃ (Aib)); 1.8 (s1,2H, NH₂); 2.95-3.15 (m, 6H, 2 (CH₂)_(β) and NHCH₂CH₃); 4.43 (m, 1H,CH_(α)); 5.39 (m, 1H, CH_(α′)); 6.02 (m, 1H); 6.22 (m, 1H); 6.9-7.56 (m,10H, indoles); 8 (m, 1H); 8.31 (m, 1H); 10.77 and 10.79 (2s, 2H, 2N¹H).Mass Spectrometry (Electrospray), m/z 518.4 [M+H]⁺; 540.3 [M+Na]⁺.Analytic HPLC (Symmetry shield 3.5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 15 min), tr=7.12 min, 99%.Freezedried Compound.

Example 59 N-Me-Aib-(D)-Trp-(D)-gTrp-C(O)NHCH₂CH₃ Example 60H-Aib-(R)-Me-Trp-(D)-gTrp-formyl Example 61H-Aib-(D)-Trp-(R)-Me-gTrp-formyl Example 62H-Me-Aib-(D)-Trp-(R)-Me-gTrp-acetyl Example 63 Evaluation of the GrowthHormone Releasing Activity of New Growth Hormone Secretagogues in theInfant Rat

Animals

Male 10-day-old Sprague Dawley rats, about 25 g body weight were used.

Pups were received on the fifth day after birth and were housed undercontrolled conditions (22±2° C., 65% humidity and artificial light from06.00 to 20.00 h). A standard dry diet and water were available adlibitum to the dams.

Experimental Procedure

One hour before the experiments, pups were separated from theirrespective dams and were divided randomly into groups of eight each.

Pups were acutely challenged subcutaneously with 100 μl of solvent(DMSO, final dilution 1:300 in physiological saline), hexarelin(Tyr-Ala-His-D-Mrp-Ala-Trp-D-Phe-Lys-NH₂, used as a reference drug), ornew compounds (300 μg/kg) and killed by decapitation 15 min later.

Trunk blood was collected and centrifuged immediately. Plasma sampleswere stored at −20° C. until assayed for the determination of plasma GHconcentrations.

Growth hormone concentrations in plasma were measured by RIA usingmaterials provided by the National Institute of Diabetes, Digestive andKidney Diseases (NIDDK) of the National Institute of Health U.S.A.

Values were expressed in terms of the NIDDK-rat-GH-RP-2 standard(potency 21 U/mg) as ng/ml of plasma.

The minimum detectable value of rat GH was about 1.0 ng/ml, andintraassay variability was about 6%.

The obtained results of several test series, wherein the in vivoactivity in the rat was determined, are listed in tables 1 to 10.

TABLE 1 Example Structure GH ng/ml  1 H-Aib-D-Trp-D-gTrp-CHO 158.8 ±39.4  13 H-Aib-D-Trp-gTrp-CHO  58 ± 6.3 SOLVENT 15.0 ± 8.0  HEXARELINTyr-Ala-His-D-Mrp-Ala-Trp-D-Phe-  202 ± 32.7 Lys-NH₂

TABLE 2 Example Structure GH ng/ml 3 N-Me-Aib-D-Trp-D-gTrp-CHO  86.6 ±12.6 4 H-Aib-D-Trp-D-gTrp-C(O)CH₃ 104.7 ± 13.5 5N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃ 175.5 ± 37.2 SOLVENT 20.7 ± 0.9 HEXARELINTyr-Ala-His-D-Mrp-Ala-Trp-D-Phe- 134.5 ± 27.2 Lys-NH₂

TABLE 3 Example Structure GH ng/ml  6 Pip-D-Trp-D-gTrp-CHO 109.7 ± 10.1 7 Pip-D-Trp-D-gTrp-C(O)CH₃ 53.1 ± 6.6  8 Isonipecotyl-D-Trp-D-gTrp-CHO94.2 ± 8.6  9 Isonipecotyl-D-Trp-D-gTrp-C(O)CH₃  61.2 ± 10.8 19Aib-D-Trp-gTrp-CO-CH₂-CH₃  79.8 ± 22.4 20Aib-D-Trp-gTrp-CO-Piperidin-4-yl 153.6 ± 30.6 SOLVENT 22.3 ± 5  HEXARELIN Tyr-Ala-His-D-Mrp-Ala-Trp-D-Phe- 114.7 ± 8.4  Lys-NH₂

TABLE 4 Example Structure GH ng/ml 39 N-Me-Aib-D-Trp-D-gTrp- 97.1 ± 21.0Isonipecotyl 40 N-Me-Aib-D-Trp-N-Me-D-gTrp- 188.2 ± 28.5  C(O)CH₃ 41H-Aib-D-Trp-N-Me-D-gTrp- 75.4 ± 15.0 C(O)CH₃ SOLVENT 10.55 ± 2.65 HEXARELIN Tyr-Ala-His-D-Mrp-Ala-Trp-D-Phe- 114.5 ± 12.9  Lys-NH₂

TABLE 5 Example Structure GH ng/ml 42 H-Aib-(D)-1-Nal-g-(D)-1-Nal-formyl25.05 ± 06.00 43 H-Aib-(D)-2-Nal-g-(D)-2-Nal-formyl 37.33 ± 19.74 44H-Aib-(D)-1-Nal-g-(D)-1-Trp-formyl 15.04 ± 03.30 45H-Aib-(D)-2-Nal-g-(D)-1-Trp-formyl 13.91 ± 03.87 46H-Aib-(D)-Trp-g-(D)-1-Nal-formyl  8.26 ± 01.09 47H-Aib-(D)-Trp-g-(D)-2-Nal-formyl  9.04 ± 04.03 SOLVENT  6.49 ± 01.18HEXARELIN 276.01 ± 23.5 

TABLE 6 Example Structure GH ng/ml 48 H-Aib-(D)-Trp-g-3(R/S)Dht-formyl17.49 ± 2.40 49 H-Aib-(D)-3(R/S)Dht-(D)-Trp-formyl 24.35 ± 4.85 50N-Me-Aib-(D)-Trp-(D)-3(R/S)Dht-acetyl 11.17 ± 1.35 51H-Me-Aib-(D)-3(R/S)Dht-(D)-Trp-acetyl 19.38 ± 4.16 SOLVENT 14.65 ± 0.92HEXARELIN 91.61 ± 4.09

TABLE 7 Example Structure GH ng/ml 52 N(Me)₂-Aib-(D)-Trp-(D)-gTrp-121.43 ± 29    formyl 53 N(Me)₂-Aib-(D)-Trp-(D)-gTrp-acetyl 26.80 ±5.64  SOLVENT 7.89 ± 1.77 HEXARELIN 172.5 ± 38.53

TABLE 8 Example Structure GH ng/ml 60 H-Aib-(R)-Me-Trp-(D)-gTrp-formyl21.02 ± 3.43 61 H-Aib-(D)-Trp-(R)-Me-gTrp-formyl 152.28 ± 43.76 62H-Me-Aib-(D)-Trp-(R)-Me-gTrp-acetyl 171.78 ± 10.32 SOLVENT  7.89 ± 1.77HEXARELIN  172.5 ± 38.53

TABLE 9 Example Structure GH ng/ml 54 H-Acc³-(D)-Trp-(D)-gTrp-formyl7.89 ± 3.20 55 H-Acc⁵-(D)-Trp-(D)-gTrp-formyl 11.46 ± 1.18  56H-Acc⁶-(D)-Trp-(D)-gTrp-formyl 8.49 ± 0.40 57H-Dpg-(D)-Trp-(D)-gTrp-formyl 18.38 ± 2.88  SOLVENT 17.32 ± 1.70 HEXARELIN 89.91 ± 3.04 

TABLE 10 Example Structure GH ng/ml 58 H-Aib-(D)-Trp-(D)-gTrp- 376.48 ±43.24  C(O)NHCH₂CH₃ 59 N-Me-Aib-(D)-Trp-(D)-gTrp- 179.53 ± 24.65 C(O)NHCH₂CH₃ SOLVENT 7.89 ± 1.77 HEXARELIN 172.5 ± 38.53

Furthermore the time dependence of the oral activity in the dog (1mg/kg; per os) was estimated for example 1 (H-Aib-D-Trp-D-gTrp-CHO).Well-trained beagles of either sex, >10 year, 10-15 kg by weight, wereused. Animals were fed normal dry food with water ad libitum and were ona 12 h-light/12 h-dark regimen with on at 7.00. The compound wasadministered orally to the dogs which had fasted since 16.00 of thepreceding day. Blood samples were taken 20 min before administration, atadministration and 15, 30, 60, 90, 120 and 180 min after administration.The results are given in table 11.

TABLE 11 NAME OF THE DOG Example RAZ FORREST MEAN 1 DAKOTA JORMA DEGANLEE MARKUS TAYLOR VALUE SEM t (min) Concentration GH (ng/ml) −20   0.483.58 2.14 1.43 2.45 2.32 2.07 0.38  0 0.35 2.75 1.64 2.01 2.55 1.41 1.791.03 15 2.11 8.91 3.58 6.38 6.11 4.8 5.32 1.02 30 0.54 6.85 6.37 8.486.9 3.89 5.5 1.07 60 0.17 2.65 3.02 4.41 6.51 4.34 3.52 0.84 90 0.4 2.472.61 6.42 5.18 4.43 3.59 0.66 120  3.58 2.48 1.94 3.71 4.54 4.28 3.420.38 180  3.46 2.82 1.49 3.18 4.12 3.18 3.04 0.36 AUC 328.53 658.38510.64 888.91 944.26 721.34 675.35 94.47 SEM = Standard deviation AUC =Area under the curve

1. Compounds of the formula I

wherein * means a carbon atom which, when a chiral carbon atom, has a Ror S configuration, one of R¹ and R³ is an hydrogen atom and the otheris a group of formula II

R² is a hydrogen atom, a linear or branched C₁-C₆ alkyl group, an arylgroup, a heterocyclic group, a cycloalkyl group, a (CH₂)_(n)-aryl group,a (CH₂)_(n)-heterocyclic group, a (CH₂)_(n)-cycloalkyl group, amethylsulfonyl group, a phenylsulfonyl group, a C(O)R⁸ group or a groupaccording to one of formulas III to VIII:

R⁴ is a hydrogen atom or a linear or branched C₁-C₄ alkyl group, R⁵ is ahydrogen atom, a linear or branched C₁-C₄ alkyl group, a (CH₂)_(n)-arylgroup, a (CH₂)_(n)-heterocyclic group, a (CH₂)_(n)-cycloalkyl group oran amino group, R₆ and R₇ are independently from each other a hydrogenatom or a linear or branched C₁-C₄-alkyl group, R₈ is a linear orbranched C₁-C₆-alkyl group, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆are independently from each other a hydrogen atom or a linear orbranched C₁-C₄-alkyl group, m is 0, 1 or 2 and n is 1 or
 2. 2. Compoundsaccording to claim 1, wherein R² is hydrogen, R³ is a group of formulaII and m is
 0. 3. Compounds according to claim 2, wherein the linear orbranched C₁-C₄ alkyl group is methyl, the linear or branched C₁-C₆ alkylgroup is methyl, ethyl or i-butyl, aryl is phenyl or naphthyl,cycloalkyl is cyclohexyl and the heterocyclic group is a 4-piperidinylor 3-pyrrolyl group.
 4. A compound having the following structure:


5. A pharmaceutical composition, comprising a therapeutically effectiveamount of the compound of claim
 1. 6. The composition of claim 5, incombination with a pharmaceutically acceptable carrier.
 7. Thecomposition of claim 5, in combination with an additional growth hormonesecretagogue.
 8. A method for elevating the plasma level of growthhormone in a mammal comprising administering to a mammal an amounteffective of the compound according to claim 1 so as to elevate theplasma level of growth hormone.
 9. A method for the treatment of growthhormone secretion deficiency comprising administering to a mammal inneed thereof a therapeutically effective amount of the compoundaccording to claim 1 so as to treat the growth hormone secretiondeficiency.
 10. A method for the treatment of growth retardation in achild in need thereof comprising administering to said child atherapeutically effective amount of the compound according to claim 1 soas to treat the growth retardation.
 11. A method for the treatment ofmetabolic disorders associated with growth hormone secretion deficiencycomprising administering to a patient in need thereof a therapeuticallyeffective amount of the compound according to claim 1 so as to treat themetabolic disorder.
 12. The method of claim 11, wherein the patient iselderly.
 13. A method for promoting wound healing, or recovery fromsurgery, which comprises administering a therapeutically effectiveamount of the compound according to claim 1 so as to promote the healingor recovery.
 14. The method of claim 13, wherein the method comprisespromoting wound healing.
 15. The method of claim 13, wherein the methodcomprises promoting recovery from surgery.
 16. The compound of claim 1,wherein R⁵ is the amino group which comprises —NH—CH₂—CH₃.
 17. Thecompound of claim 16, wherein the compound isH-Aib-(D)-Trp-(D)-gTrp-C(O)NHCH₂—CH₃ orN-Me-Aib-(D)-Trp-(D)-gTrp-C(O)NHCH₂—CH₃.